Biomarker-based treatment stratification in ADHD: An out-of-sample validation

Abstract Attention-deficit/hyperactivity disorder (ADHD) is characterized by neurobiological heterogeneity, possibly explaining why not all patients benefit from a given treatment. As a means to select the right treatment (stratification), biomarkers may aid in personalizing treatment prescription, thereby increasing remission rates.The present study introduces a clinically interpretable and actionable, age- and sex-standardized biomarker based on individual alpha peak frequency (iAPF) assessed during resting-state electroencephalography (EEG). The biomarker was developed in a heterogeneous sample (N=4249), and stratifies patients with a higher iAPF to Methylphenidate (MPH; N=336) and those with a lower iAPF to Neurofeedback (NFB; N=136), resulting in a predicted gain in normalized remission of 17-30%. Blinded out-of-sample validation studies for MPH (N=58) and NFB (N=96) corroborated these findings, yielding a predicted gain in stratified normalized remission of 36% and 29%, respectively.These findings suggest that acknowledging neurobiological heterogeneity can inform stratification of patients to their individual best treatment and enhance remission rates.